Microfluidic system including a bubble valve for regulating fluid flow through a microchannel

ABSTRACT

A microfluidic system includes a bubble valve for regulating fluid flow through a microchannel. The bubble valve includes a fluid meniscus interfacing the microchannel interior and an actuator for deflecting the membrane into the microchannel interior to regulate fluid flow. The actuator generates a gas bubble in a liquid in the microchannel when a sufficient pressure is generated on the membrane.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/179,586 filed Jun. 24, 2002, which claims priority to U.S.Provisional Patent Application No. 60/373,256 entitled “MicrofluidicSystem Including a Bubble Valve for Regulating Fluid Flow Through aMicrochannel” filed Apr. 17, 2002; and is related to U.S. patentapplication Ser. No. 10/179,488, entitled “Method and Apparatus forSorting Particles”, filed Jun. 24, 2002. The contents of bothapplications are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to microscale fluid handling devices andsystems. More particularly, the present invention relates to a methodand system for controlling liquid flow in a microchannel by theintroduction of a gas bubble to a microfluidic system.

BACKGROUND OF THE INVENTION

In the chemical, biomedical, bioscience and pharmaceutical industries,it has become increasingly desirable to perform large numbers ofchemical operations, such as reactions, separations and subsequentdetection steps, in a highly parallel fashion. The high throughputsynthesis, screening and analysis of (bio)chemical compounds, enablesthe economic discovery of new drugs and drug candidates, and theimplementation of sophisticated medical diagnostic equipment. Of keyimportance for the improvement of the chemical operations required inthese applications are an increased speed, enhanced reproducibility,decreased consumption of expensive samples and reagents, and thereduction of waste materials.

Microfluidic devices and systems provide improved methods of performingchemical, biochemical and biological analysis and synthesis.Microfluidic devices and systems allow for the performance ofmulti-step, multi-species chemical operations in chip-based microchemical analysis systems. Chip-based microfluidic systems generallycomprise conventional ‘microfluidic’ elements, particularly capable ofhandling and analyzing chemical and biological specimens. Typically, theterm microfluidic in the art refers to systems or devices having anetwork of processing nodes, chambers and reservoirs connected bychannels, in which the channels have typical cross-sectional dimensionsin the range between about 1.0 μm and about 500 μm. In the art, channelshaving these cross-sectional dimensions are referred to as‘microchannels’.

By performing the chemical operations in a microfluidic system,potentially a number of the above-mentioned desirable improvements canbe realized. Downscaling dimensions allows for diffusional processes,such as heating, cooling and passive transport of species (diffusionalmass-transport), to proceed faster. One example is the thermalprocessing of liquids, which is typically a required step in chemicalsynthesis and analysis. In comparison with the heating and cooling ofliquids in beakers as performed in a conventional laboratory setting,the thermal processing of liquids is accelerated in a microchannel dueto reduced diffusional distances. Another example of the efficiency ofmicrofluidic systems is the mixing of dissolved species in a liquid, aprocess that is also diffusion limited. Downscaling the typicaldimensions of the mixing chamber thereby reduces the typical distance tobe overcome by diffusional mass-transport, and consequently results in areduction of mixing times. Like thermal processing, the mixing ofdissolved chemical species, such as reagents, with a sample orprecursors for a synthesis step, is an operation that is required invirtually all chemical synthesis and analysis processes. Therefore, theability to reduce the time involved in mixing provides significantadvantages to most chemical synthesis and analysis processes.

Another aspect of the reduction of dimensions is the reduction ofrequired volumes of sample, reagents, precursors and other often veryexpensive chemical substances. Milliliter-sized systems typicallyrequire milliliter volumes of these substances, while microliter sizedmicrofluidic systems only require microliters volumes. The ability toperform these processes using smaller volumes results in significantcost savings, allowing the economic operation of chemical synthesis andanalysis operations. As a consequence of the reduced volume requirement,the amount of chemical waste produced during the chemical operations iscorrespondingly reduced.

In microfluidic systems, regulation of minute fluid flows through amicrochannel is of prime importance, as the processes performed in thesesystems highly depend on the delivery and movement of various liquidssuch as sample and reagents. A flow control device may be used toregulate the flow of liquid through a microchannel. Regulation includescontrol of flow rate, impeding of flow, switching of flows betweenvarious input channels and output channels as well as volumetric dosing.

U.S. Pat. No. 6,062,681 describes a bubble valve for a liquid flowchannel in which the flow of a liquid is controlled by the generation ofa gas bubble in the channel using a heater placed in the liquid. As theheater is activated, a bubble is formed which can be enlarged or reducedin size by increasing or decreasing, respectively, the temperature ofthe heater. The described system presents a number of disadvantages,namely, the required power to operate the valve and the inherentrequirement that liquid in the channel be heated upon passing the valve.Even small increases in liquid temperature, by only a couple of degrees,can have disastrous effects on the highly heat sensitive biochemicalsubstances present in the liquids to be controlled in many microfluidicsystems. In addition, the required on-chip electric circuitry for theheater increases the complexity of the described valve and consequentlyresults in unacceptably high costs, particularly if the fluidic systememploying the bubble valve only used for a single application.

Other valves in the prior art use electrochemical means to produce abubble in a liquid.

SUMMARY OF THE INVENTION

The present invention provides a bubble valve for controlling,regulating or varying fluid flow through a microfluidic system. Thebubble valve regulates fluid flow through a channel using an externallyoperated mechanical or pneumatic actuator. The actuator causes adeflection of a fluid meniscus into the interior of the channel toregulate liquid flow. The actuator may mechanically force a gas bubbleinto a fluid carrying microchannel to inhibit liquid flow or to causeliquid flow by applying a sufficiently high pressure to the meniscus.The bubble valve effectively controls the flow of liquids inmicrofluidic systems, without heating the fluid and without complexon-chip circuitry.

The microfluidic system includes a microchannel and a sealed, gas-filledreservoir positioned adjacent to and connected to the microchannel. Thegas filled reservoir has a movable wall and a meniscus formed by aliquid in the microchannel that forms an interface between the reservoirand the microchannel interior. The meniscus may form a portion of theside wall of the microchannel. An external mechanical actuator may beused to deflect the movable wall of the reservoir. As the movable wallis deflected, the volume of the reservoir decreases and the gas pressureinside the reservoir increases, causing the meniscus to deflect into themicrochannel, thereby modifying the cross-sectional area of themicrochannel and consequently varying the flow of liquid through thechannel. The increased pressure in the reservoir pushes gas from thereservoir into the microchannel. The gas may result in a local gasbubble being forced into the microchannel from the gas-filled reservoir.The resulting gas bubble occupies a portion of the cross-section of thechannel, allowing liquid flow through the channel to be effectivelycontrolled by controlling the size of the gas bubble via the externalactuator.

The meniscus may comprise a virtual wall formed in a side wall of themicrochannel. The virtual wall is a meniscus formed by a liquid in themicrochannel that fills an aperture formed in the side wall of themicrochannel and essentially replaces the removed portion of the sidewall without affecting the properties of liquid flow through thechannel. A gas bubble can be forced into the channel by applying a gaspressure at the opening using an external pneumatic actuator. The gaspressure forces the meniscus inside the channel, which varies the flowof liquid through the channel interior.

According to one embodiment, the microchannel includes a hydrophobicpatch spanning the width of the microchannel at the location where thegas bubble is introduced to enhanced on-off switching of the bubblevalve. The hydrophobic patch anchors the bubble in a particular locationin the microchannel. If the introduced gas bubble covers the whole areaof the patch, the bubble is effectively retained by capillary forces andblocks any liquid flow up to a certain pressure difference, depending onthe level of hydrophobicity of the patch.

Alternatively or in combination with a hydrophobic patch, themicrochannel can be locally shaped into a cavity for receiving andanchoring the gas bubble. By providing an appropriate cavity, the bubblecan be kept in place during operation, reducing the risk that the gasbubble is carried away with the liquid.

According to one aspect of the invention, a microfluidic device isprovided. The microfluidic device comprises a microchannel having aninterior bounded by a side wall and a valve for regulating the flow offluid through the microchannel. The valve comprises a gas-filledreservoir, a fluid meniscus interfacing the reservoir and the interiorand an actuator for varying the volume of the reservoir to increase aninternal pressure of the reservoir to vary the flow of liquid throughthe channel.

According to another aspect, a microfluidic device is provided,comprising a first plate having a groove formed therein defining amicrochannel, a second plate for enclosing the microchannel and aflexible membrane. The second plate is bonded to the first plate and hasan aperture adjacent to the groove sized and dimensioned to form ameniscus when the microchannel is filled with a liquid. The aperturedefines a reservoir adjacent to the microchannel, wherein the meniscusforms an interface between the microchannel and the reservoir. Theflexible membrane is bonded to the second plate to seal the reservoir.

According to another aspect, a method of making a bubble valve isprovided, the method comprises providing a microchannel having aninterior bounded by a side wall, an aperture formed in the side wall anda valve chamber adjacent to the aperture in communication with theinterior, filling the microchannel with a liquid to form a meniscus ofthe liquid in the aperture, whereby the step of filling traps a gas inthe valve chamber and providing an actuator for increasing the pressurein the valve chamber to deflect the meniscus into the interior.

According to yet another aspect, a method of making a bubble valve isprovided. The method comprises providing a microchannel having aninterior bounded by a side wall, an aperture formed in the side wall anda valve chamber adjacent to the aperture in communication with theinterior, filling the microchannel with a liquid to form a meniscus ofthe liquid in the aperture and applying and sealing an actuatorcomprising a chamber to a top surface of the microchannel to form agas-filled chamber adjacent to the meniscus. The actuator varies thepressure in the gas-filled chamber to deflect the meniscus into theinterior, thereby regulating fluid flow.

According to still another aspect, a microfluidic device is providedcomprising a microchannel having an interior bounded by a side wall, abubble valve for creating and injecting a bubble into the microchannelinterior to regulate fluid flow through the microchannel and ahydrophobic patch for retaining the bubble in a predetermined positionin the microchannel interior.

According to yet another aspect a bubble valve in a particle sortingdevice for separating particles having a predetermined characteristicfrom particles not having a predetermined characteristic is provided.The bubble valve comprises a gas-filled reservoir, a side channel incommunication with a channel through which a stream of particles in acarrier fluid passes, wherein the carrier fluid forms a meniscus in theside channel adjacent to the gas-filled reservoir and an actuator fordeflecting the meniscus to create a pressure pulse to selectivelydeflect a particle having the predetermined characteristic from thestream of particles.

According to still another aspect, a method of varying an electricalresistance in a microchannel is provided. The method comprisesgenerating a bubble and injecting the bubble into a liquid in themicrochannel, whereby the bubble varies the electrical resistance of themicrochannel.

According to yet another aspect, an electrophoretic system is provided,comprising an electrokinetically operated microchannel, a sample wellfor providing an sample to the microchannel, a voltage source and abubble valve for injecting a bubble into the microchannel to vary theelectrical resistance of the microchannel.

According to a final aspect of the invention, an electrokinetic columnto column switch is provided, comprising a first electrokineticallyoperated microchannel, a second electrokinetically operated microchannelin communication with the first electrokinetically operated microchanneland a bubble valve for selectively blocking flow from the firstelectrokinetically operated microchannel to the secondelectrokinetically operated microchannel by selectively injecting abubble into a microchannel.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a microfluidic system suitable forimplementing the illustrative embodiment of the invention.

FIG. 2 shows an exploded view of a bubble valve according to anillustrative embodiment of the present invention.

FIG. 3 shows an isometric view of the bubble valve of FIG. 2.

FIG. 4 shows a top view of the bubble valve of FIG. 2.

FIGS. 5 a-c are cross-sectional views of the bubble valve of FIG. 2 inoperation.

FIG. 6 shows an exploded view of an alternative embodiment of a bubblevalve according to the present invention.

FIG. 7 shows a top view of the bubble valve of FIG. 6.

FIGS. 8 a-c are cross-sectional view of the bubble valve of FIG. 6 inoperation.

FIG. 9 shows an application of the bubble valve of an illustrativeembodiment of the present invention in a microchannel.

FIG. 10 shows a Y-intersection in a microfluidic system of an embodimentof the invention that implements a bubble valve to control liquid flowaccording to the teachings of the present invention.

FIG. 11 shows a Y-intersection in a microfluidic system of anotherembodiment of the invention that implements a bubble valve to controlliquid flow according to the teachings of the present invention.

FIGS. 12 a-c shows an electrophoresis system that implements a bubblevalve to control electrical current during electrokinetic injectionaccording to the teachings of the present invention.

FIG. 13 a shows an electrokinetic column-column switch implementing abubble valve according to the teachings of the present invention.

FIG. 13 b shows an alternate electrokinetic column-column switchimplementing a bubble valve according to another embodiment of thepresent invention.

FIG. 14 shows a selective resistance circuit that employs a bubble valveto control electrical current according to the teachings of the presentinvention.

FIG. 15 shows an alternative selective resistance circuit that employs abubble valve to control electrical current according to the teachings ofthe present invention.

FIG. 16 shows a particle sorting system that implements a bubble valveof the present invention to produce fluid impulses to sort particles.

FIGS. 17 a, 17 b and 17 c illustrate the operation of the particlesorting system of FIG. 16.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved bubble valve for controllingfluid flow through a microchannel in a microfluidic system. Theinvention further provides a method of forming the bubble valve. Thebubble valve of the present invention can be applied in numerousmicrofluidic systems for controlling and switching fluid flows. Examplesof suitable applications include, but are not limited to: flowcytometry, column switching, 2-D separations, cell or particle sortingapplications on a chip, regulating pressurized fluid flows includingon-off switching, regulating electrokinetic fluid flows andelectrokinetically induced processes including on-off switching andelectrokinetic sample injection and channel to channel switching.

FIG. 1 illustrates a microfluidic system suitable for implementing theillustrative embodiment of the present invention. The illustrativemicrofluidic system 100 comprises a substrate 101 having one or moremicrochannels 21 disposed therein. The microchannels transport fluidthrough the microfluidic system 100 for processing, handling, and/orperforming any suitable operation on a liquid sample. As used herein,the term “microfluidic” refers to a system or device for handling,processing, ejecting and/or analyzing a fluid sample including at leastone channel having microscale dimensions. The term “channel” as usedherein refers to a pathway formed in or through a medium that allows formovement of fluids, such as liquids and gases. The term “microchannel”refers to a channel preferably formed in a microfluidic system or devicehaving cross-sectional dimensions in the range between about 1.0 μm andabout 500 μm, preferably between about 25 μm and about 250 μm and mostpreferably between about 50 μm and about 100 μm. One of ordinary skillin the art will be able to determine an appropriate volume and length ofthe microchannel. The ranges are intended to include the above-recitedvalues as upper or lower limits. The microchannel can have any selectedshape or arrangement, examples of which include a linear or non-linearconfiguration and a U-shaped configuration. The microfluidic system 100may comprise any suitable number of microchannels 21 for transportingfluids through the microfluidic system 100.

The microfluidic system 100 includes a bubble valve 10, 10′ shown inFIGS. 2-8 c for controlling liquid flow through a microchannel of thesystem. According to the illustrative embodiment, the microchannel isdefined by a side wall having any suitable shape enclosing at least aportion of the interior of the channel. The bubble valve may be formedby a gas-filled reservoir positioned adjacent to the microchannelincluding a meniscus that forms the interface between the reservoir andthe microchannel interior. The meniscus may form a portion of the sidewall of the microchannel. The bubble valve includes an actuator formodifying the pressure in the reservoir to deflect the meniscus into thechannel interior, thereby modifying the cross-sectional area of themicrochannel and consequently varying the flow of liquid through thechannel.

According to an alternate embodiment, the bubble valve is formed by ameniscus in a separate side channel that communicates with andintersects a microchannel through which a liquid to be controlled flows.One skilled in the art will recognize that the meniscus can be locatedat any location relative to the microchannel through which liquid flows.

The gas-filled reservoir may be formed when filling the microchannelhaving an aperture in a side wall and a reservoir formed adjacent to theaperture. An empty microchannel may be filled with liquid, forming themeniscus in the aperture, which traps the gas that forms the gas bubbleand forms a gas pocket in the reservoir adjacent to the meniscus. Thecreation of the gas pocket on filling provides a sterile gas bubble andreduces contaminants in the system. Alternatively, the air pocket may becreated by introducing a gas to the reservoir after filling of themicrochannel.

FIG. 2 shows an exploded view of an embodiment of an illustrative bubblevalve 10 of the present invention. The microfluidic system may be formedby a plurality of stacked layers. As shown in FIG. 2, the illustrativemicrofluidic system 100 includes a first plate 20 in which a groovedefining the microchannel 21 is provided. A hydrophobic patch 22 may beapplied to an inner wall of the microchannel 21. A second plate 30 forenclosing the microchannel is bonded to the first plate 20 and includesan aperture 31. A third plate 40 is bonded on top of second plate 30 toclose and seal the stacked structure. The aperture 31 of theintermediate second plate 30 defines a void in the system adjacent tothe microchannel 21.

FIGS. 3 and 4 illustrates the assembled bubble valve 10. As shown, thestacked first plate 20, second plate 30 and third plate 40 define aclosed, gas filled gas reservoir 70, which can be actuated with adisplacement actuator 50. According to the illustrative embodiment, theaperture 31 defining the reservoir 70 comprises a main body 31 a and aslot 31 b extending from the main body 31 a. When the microfluidicsystem 10 is assembled, the slot 31 b of the aperture 31 defines a gapin the side wall of the microchannel 21 that provides access to andcommunicates with the interior of the microchannel 21.

The bubble valve 10 operates to control the flow of liquid through themicrochannel 21. A meniscus is formed in the aperture 31, whichinterfaces with and separates the microchannel interior from thereservoir 70. According to the embodiment shown in FIGS. 2-8 c, themeniscus is formed by a liquid filling the microchannel in the slot 31b. One skilled in the art will recognize that other suitable devices maybe used to form the meniscus. The liquid in the slot 31 b is retained inthe microchannel by capillary forces. The actuator 50 deflects the upperwall of the reservoir, defined by plate 40, which decreases the volumeof the reservoir 70. The actuator 50 may comprise any suitable devicefor deflecting the wall, such as an electromagnetic actuator or apiezoelectric element. The plate 40 may comprises a flexible membrane.The decreased volume consequently increases the pressure of thereservoir 70 and causes the meniscus 80 to deflect into the channelinterior to create a constriction in the channel, thereby impeding fluidflow or pushing fluid away from the meniscus. If a sufficient pressureis applied to the meniscus, the actuator generates and enlarges a bubblein the liquid of the microchannel, which blocks fluid flow. Thehydrophobic patch 22 provides an anchor for the bubble and retains thebubble at a selected location in the microchannel.

After the microchannel is filled with a liquid 60, the bubble valve 10is ready for operation. FIG. 5 a-c illustrate the operation of thebubble valve according to the teachings of the invention. FIG. 5 a showsthe bubble valve in an ‘open’ state. According to the embodiment ofFIGS. 5 a-5 c, the meniscus between the reservoir and the interior ofthe microchannel is defined by the meniscus 80, formed by the liquid 60in the slot 31 b in the second plate 30. In the ‘open’ state, liquidflows freely through the microchannel 21 and the valve does not imposeany additional flow resistance in the channel.

The slot 31 b may be sized and dimensioned to form a “virtual wall” inthe microchannel. As used herein, “virtual wall” refers to the meniscus80 formed by the first liquid 60 in the aperture formed in the side wallof the microchannel 20, which essentially replaces the removed portionof the side wall without affecting the properties of the microchannel.The meniscus surface can be, although not required, substantiallyco-planar with the wall of the microchannel in which the meniscus isformed. The word “virtual” is chosen to express the effect that theoverall liquid flow through the microchannel 21 of the microfluidicsystem 100 is not influenced by the virtual wall, i.e. the flow ofliquid in the microfluidic system having a virtual wall is substantiallyidentical to the flow of liquid through an identical microfluidic systemin which no virtual wall is present. One of ordinary skill willrecognize that the meniscus may be convex or concave, depending on theappropriate system pressure.

When the actuator 50 is actuated, the bubble valve 10 switches to a“pinched” state, as shown in FIG. 5 b, to inhibit fluid flow through thechannel interior. In the ‘pinched’ state, the actuator 50 deflects thetop of the gas reservoir 70 for a certain fraction, increasing thepressure in the reservoir 70 and forcing the meniscus 80 down into thechannel 21. The deflection of the meniscus locally reduces thecross-section of the channel 21 and introduces an additional flowresistance to the liquid flow. The degree of reduction in the liquidflow through the microchannel corresponds to the amplitude, frequencyand duration of the displacement of the meniscus 80, which arecontrollable by the actuator 50. One skilled in the art will recognizethat any suitable means for varying the pressure within the reservoir 70may be used to deflect the meniscus 80, thereby regulating fluid flow.

When the actuator is fully actuated, the bubble valve 10 is switched toa closed state, as illustrated in FIG. 5 c. As shown, in the closedstate, the meniscus 80 deflects fully to form and introduce a gas bubble81 into the microchannel 21. The gas bubble 81 is retained by thehydrophobic patch 22 formed in the channel wall opposite the slot 31 b.As a result, the liquid flow in the channel is substantially blocked. Byreducing the pressure on the meniscus 80, the bubble valve 10 can bebrought from the ‘closed’ state of FIG. 5 c via the ‘pinched’ state ofFIG. 5 b back to the ‘open’ state of FIG. 5 a.

According to one embodiment, the bubble valve 10 may be used as a checkvalve for regulating pressure in the microchannel. When the pressure inthe microchannel exceeds a maximum breaking pressure, the bubblecollapses, opening the valve and allowing fluid to flow through thechannel, thereby reducing the pressure in the microchannel. The breakingpressure depends on the hydrophobicity of the hydrophobic patch 22, aswell as the geometry of the microchannel.

Alternatively or in combination with the hydrophobic patch 22, themicrochannel 21 can be locally shaped into a cavity for receiving andanchoring the gas bubble 81. By providing an appropriate cavity, thebubble can be kept in place during operation, reducing the risk that thegas bubble is carried away with the liquid.

According to the embodiments shown in FIGS. 2-5 c, the actuator 50 isintegrated in the microfluidic chip 100. However, one skilled in the artwill recognize that an external, reusable actuator may also be used tocontrol formation of a gas bubble in the microchannel.

FIG. 6 shows an alternative embodiment of a microfluidic system 100′including a bubble valve 10′ having an external actuator 90 according tothe teachings of the invention. In the embodiment shown in FIG. 6, themicrofluidic system 100′ includes a first plate 200 including a groovedefining the microchannel 210 and a second plate 300 bonded to the firstplate 200 for enclosing the microchannel 210 and in which a virtual wallopening 32 is formed. The virtual wall opening 32 is sized anddimensioned to form a “virtual wall” when the microchannel 210 is filledwith a liquid.

Upon filling of the microchannel 21 with a liquid, a virtual wall 32 ais formed in virtual wall opening 32. As shown in FIGS. 7, 8 a-8 c, themicrofluidic system further includes an external actuator, illustratedas pressurizer 90, pressed and sealed onto the top of the second plate300 to form a tight seal. The external pressurizer 90 defines a sealedpressurizing chamber 92 adjacent to the virtual wall 32 a. Thepressurizer varies the pressure within the pressurizing chamber 92 tocontrol liquid flow through the microchannel 210 by modifying theposition of the virtual wall. The pressurizer 90 may include a source ofpressurized gas (not shown) and a gas inlet 91 to allow a gas pressureto be applied to the virtual wall 32 a in order to move the virtualwall. The pressurizer may alternatively include a flexible wall thatdeflects to vary the volume of the chamber 92 upon activation of anactuator, such as a piezoelectric element or electromagnetic actuator.

FIG. 8 a shows a cross-section of the bubble valve 10′ of FIGS. 6 and 7in the ‘open’ state. As shown, when the microchannel 210 is filled withliquid 600, a virtual wall 32 a, defined by a meniscus 800, is formedwithin the virtual wall opening 32. The meniscus essentially replacesthe absent portion of the side wall of the microchannel and allowsliquid to flow through the channel interior unimpeded and uninfluencedby the virtual wall.

FIG. 8 b depicts the ‘pinched’ state of the bubble valve, when thepressurizer 90 is activated. As shown, activation of the pressurizer 90increases the internal pressure within the pressurizing chamber 92. Theincreased pressure moves the meniscus 800 down the channel height andinto the microchannel interior, thereby regulating liquid flow. Thepressurized controls the level of the internal pressure in order tocontrol the amount of deflection of the meniscus and therefore the rateof fluid flow.

To switch the valve to a ‘closed’ state, as shown in FIG. 8 c, thepressurizer 90 applies a large pressure that is sufficient to form andintroduce a gas bubble 810 into the channel 210. The hydrophobic patch220 retains the gas bubble 810 in place. As a result, the liquid flow inthe channel is blocked up to a ‘breaking pressure’, which depends on thehydrophobicity of hydrophobic patch 220. A higher hydrophobicity resultsin a larger breaking pressure. By reducing the pressure on the meniscus800 the bubble valve 10′ can be brought from the ‘closed’ state of FIG.8 c via the ‘pinched’ state of FIG. 8 b back to the ‘open’ state of FIG.8 a.

FIG. 9 shows an application of a bubble valve 10 for flow regulation ina microchannel 121 according to one embodiment of the invention. Duringtypical operation of a microfluidic system, a pressure difference isapplied over the length of a microchannel 121. A bubble valve 10 can beemployed to regulate the flow through the microchannel between zero anda maximum flow rate, depending on the applied pressure difference.

FIG. 10 shows a portion of a microfluidic system according to anembodiment of the invention forming a Y-intersection comprising twoinlet microchannels 121 a and 121 b and an outlet channel 121 c thatcombines the fluids flowing through the two inlet microchannels. Thefirst microchannel 121 a carries a first liquid and the secondmicrochannel 121 b carries a second liquid. The microchannels 121 a and121 b are each controlled by a corresponding bubble valve, 10 a and 10b, respectively, for regulating the combined composition and flow ratethrough the outlet microchannel 121 c. One skilled in the art willrecognize that that the number of inlet channels is not limited to two,but is presented here merely as an example.

FIG. 11 shows a Y-intersection of a microfluidic system according toanother embodiment of the invention. As shown the Y-intersectioncomprises an inlet microchannel 221 c and two outlet microchannels 221 aand 221 b for splitting the incoming liquid flow from the inletmicrochannel 221 c. The flow of each outlet channel is regulated by acorresponding bubble valve 200 a and 200 b, respectively. The incomingliquid flow from the inlet microchannel 221 c can be split betweenmicrochannel 221 a and microchannel 221 b in any required ratio. Oneskilled in the art will recognize that that the number of inlet channelsis not limited to two, but is presented here merely as an example.

FIG. 12 a-12 c shows the implementation of an electrophoresis system 110comprising five bubble valves, 10 a-e of the present invention, arrangedwith a crossed microchannel configuration. Regulation of the bubblevalve 10 a regulates the electric current through the associatedelectrokinetically operated microchannel 115 a. The pinching of theliquid in the electrokinetically operated microchannel 115 a by a bubblevalve will result in an increased electrical resistance in themicrochannel 115 a. As a result, the migration of charged species andelectro-osmotic flow in the electrokinetically operated microchannel 115a can be regulated. A voltages difference for the injection of samplefrom a well storing a supply of a sample 125 between the bubble valve 10a and the crossing point 111 of the microchannels and consecutiveseparation are provided via wells V+ and V0. Electrodes are placed inthe V+ and V0 wells and energized with a constant voltage differenceduring the operation of the electrophoresis system.

In the injection phase, valves 10 a, 10 b, 10 c and 10 d aresubstantially in the open position, allowing passage of electricalcurrent up to a required level for injection (FIG. 12 b shows directionof current/sample), while bubble valve 10 e is closed. The valves arekept in this position long enough for the sample to move from the samplewell 125 towards and past the central injection crossing 111. Varyingthe opening ratio of valves 10 a, 10 b and 10 d can be adjusted toconfine the sample to a narrow flow through the injection cross 111, asshown in FIG. 12 c (i.e. ‘pinched injection’).

Immediately after the injection phase, a plug of sample is injected andseparated in the separation column 115 a (microchannel which runshorizontally in figure) by closing bubble valves 10 a, 10 d and 10 c andopening valves 10 b and 10 e. Now the total voltage difference isapplied longitudinally over the separation channel, resulting in theseparation of the constituents in the sample (FIG. 12 c).

FIG. 13 a illustrates another application of the bubble valve of thepresent invention implemented in a column-column switch 130 forelectrokinetically transferring a substance from a firstelectrokinetically operated microchannel 215 a to a secondelectrokinetically operated microchannel 215 b. The column-column switch130 comprises a bubble valve 10 b of the present invention that connectsthe first electrokinetically operated microchannel 215 a to the secondelectrokinetically operated microchannel 215 b. Both electrokineticallyoperated microchannel 215 a and electrokinetically operated microchannel215 b are connected to corresponding wells well 220 a-d. In thefollowing example, it is assumed that the substances electrokineticallymove from a positive electric potential to ground and that well 120 cand well 120 b are provided with a positive potential whilst well 120 aand well 120 d are grounded.

At first, the two electrokinetically operated microchannel 215 a andelectrokinetically operated microchannel 215 b are operatedindependently and the connecting bubble valve 10 b is in the ‘closed’state whilst bubble valve 10 a and bubble valve 10 c are in the ‘open’state. To electrokinetically transfer substance from electrokineticallyoperated microchannel 215 a to the electrokinetically operatedmicrochannel 215 b, bubble valve 10 a and bubble valve 10 c are switchedto the closed state, and the connecting bubble valve 10 b is openedmomentarily to allow passage of an amount of substance from theelectrokinetically operated microchannel 215 a to the electrokineticallyoperated microchannel 215 b. The amount transferred depends directlyupon the time bubble valve 10 b is opened. After the required amount ofsubstance is transferred, the connecting bubble valve 10 b is closed andthe bubble valve 10 a and bubble valve 10 b are opened again.

FIG. 13 b illustrates the implementation of another column to columnswitch 130′ to exchange liquid from a first column 215 a′ selectivelyinto a second column 215 b′. The first column and the second column areeach crossed by a transfer column 250, operated by a first bubble valve10 a arranged on one end of the transfer column 250 and a second bubblevalve 10 b arranged on the opposite end of the transfer column 250. Thefirst one of the bubble valves is attached to the first column 215 a′and is actuated upon transiently by an external actuator for increasingthe pressure within the bubble valve reservoir. Increasing the pressureon the bubble valve will deflect the meniscus 80, inducing a transientflow in the transfer column 250 from the pressurized bubble valve 10 atowards the second bubble valve 10 b, which comprises a compressiblevolume of gas. This transient flow effectively transfers a liquid volumefrom the first column 215 a′ to the second column 215 b′. Upondeactivation of the external actuator, the flow in the transfer column250 reverses as the compressed gas volume in the second bubble valve 10b exerts a pressure on the liquid in the transfer column 250.

FIG. 14 shows a selective resistance circuit employing a bubble valve ofthe present invention for selectively including a predefined electricalresistance in an electrokinetic circuit. The circuit 140 comprises aninlet microchannel 321, which splits into two paths. The first path 322includes a fluidic resistor 240 a and a bubble valve 10 a, the secondparallel path 323 includes a fluidic resistor 240 b and a bubble valve10 b. The fluidic resistors 240 a-b comprise a channel of appropriatelength to results in a certain electrical resistance. The bubble valve10 a and the bubble valve 10 b can be switched each to either on toallow fluid flow through the associated microchannel or off to blockfluid flow through the associated microchannel. As a result, the overallelectrical resistance of the electrokinetic circuit can be switchedbetween four values: infinite (both bubble valves 10 a-b are off), theresistance of fluidic resistor 240 a (bubble valve 10 a on, bubble valve10 b off), the resistance of fluidic resistor 240 b (bubble valve 10 aoff, bubble valve 10 b on) and the parallel resistance of fluidicresistor 24 a-b (both bubble valves 10 a and 10 b on).

FIG. 15 shows an alternative resistance circuit 150 according to anotherapplication of the invention, now for the selective application of avoltage. By opening either the bubble valve 10 a or bubble valve 10 b,the voltage imposed on an outgoing channel 523 can be selected. Fluidicresistor 245 a and 245 b function to limit the electric current ineither of the two states to a predetermined value.

FIG. 16 illustrates another application of the bubble valve 10 of thepresent invention in a particle sorting application, wherein the bubblevalve is positioned in a side channel that communicates with a channelthrough which particles in suspension flow. According to one applicationof the present invention, a particle sorter 160 comprises a closedchannel system of capillary size for sorting particles, such as cells.The channel system comprises a first supply duct 162 for introducing astream of particles and a second supply duct 164 for supplying a carrierliquid. The first supply duct 162 ends in a nozzle, and a stream ofparticles is introduced into the flow of carrier liquid. The firstsupply duct 162 and the second supply duct 164 enter a measurement duct166, which branches into a first branch 172 a and a second branch 172 bat a branch point 171. A measurement region 182 a is defined in themeasurement duct 166 and is associated with a detector 182 b to sense apredetermined characteristic of particles in the measurement region 182a. Two opposed bubble valves 1 Oa and 10 b are positioned incommunication with the measurement duct 166 and are spaced opposite eachother. The bubble valves 10 a, 10 b communicate with the measurementduct 166 through a pair of opposed side passages 174 a and 174 b,respectively. Liquid is allowed to partly fill these side passages 174 aand 174 b to form a meniscus 175 therein. An external actuator 176 isalso provided for actuating the bubble valves 10 a, 10 b, whichmomentarily causes a flow disturbance in the duct to deflect the flowtherein when activated by the actuator 176.

In a suspension introduced by the first supply duct 162, two types ofparticles can be distinguished, normal particles 180 a and particles ofinterest 180 b. The flow rates in both branches 172 a and 172 b areadjusted so that the stream of particles normally flows through thesecond branch 172 b. Upon sensing the predetermined characteristic inthe particles in the measurement region 182 a, the detector 182 b raisesa signal. The external actuator 176 activates the bubble valves 10 a, 10b when signaled by the detector 182 b in response to sensing thepredetermined characteristic, to create a flow disturbance in themeasurement duct 166 between the sideway passages 174 a, 174 b, todeflect the particle having the predetermined characteristic so that itflows down the first branch duct 172 a rather than the second branchduct 172 b. The detector communicates with the actuator 176, so thatwhen the detector 182 b senses a predetermined characteristic in aparticle, the actuator activates the first bubble valve 10 a to causepressure variations in the reservoir 70 of the first bubble valve. Theactivation of the first bubble valves causes a transient pressurevariation in the first side passage 174 a. The second side passage 174 band the second bubble valve 10 b absorb the transient pressurevariations in the measurement duct 166 induced via the actuator 176.Basically, the reservoir 70 b of the second bubble valve 10 b is achamber having a resilient wall or contains a compressible fluid such asa gas. The resilient properties allow the flow of liquid from themeasurement duct into the second side passage 174 b.

FIGS. 17 a-17 c illustrate the operation of the particle sorting system160 of FIG. 16. In FIG. 17 a, the detector raises a signal to activatethe actuator. Upon activation of the actuator, the pressure within thereservoir of the first bubble valve 10 a is increased, causing atransient discharge of liquid from the first side passage 174 a asindicated by the arrow. The sudden pressure increase caused at thispoint in the duct causes liquid to flow into the second side passage 174b because of the resilient properties of the reservoir of the secondbubble valve 10 b. This movement of liquid into the second side passage174 b is indicated with an arrow. Resultingly, as can be seen in thefigure, the flow through the duct is deflected causing the selectedparticle of interest 178 b located between the first side passage 174 aand the second side passage 174 b to be shifted perpendicular to itsflow direction in the normal state. The flow resistances to themeasurement duct 166, the first branch 172 a and the second branch 172 bis chosen so that the preferred direction of the flow to and from thefirst side passage 174 a and the second side passage 174 b has anappreciable component perpendicular to the normal flow through themeasurement duct 166. This goal can for instance be reached by the firstbranch 172 a and the second branch 172 b so that their resistances toflow is large in comparison with the flow resistances of the first sidepassage 174 a and the second side passage 174 b.

FIG. 17 b shows the particle sorting system 160 during the relief of thefirst bubble valve reservoir when the particle of interest 178 b hasleft the volume between the first side passage 174 a and the second sidepassage 174 b. The actuator 176 is deactivated, causing the pressureinside the reservoir to return to the normal pressure. During thisrelief phase there is a negative pressure difference between the tworeservoirs of the bubble valves, causing a liquid flow through the firstside passage 174 a and the second side passage 174 b opposite to theliquid flow shown in the previous figure and is indicated by the arrows.

FIG. 17 c shows the particle sorting system 160 after completion of theswitching sequence. The pressures inside the reservoirs of the bubblevalves has been equalized so the flow through the measurement duct 166is normalized. As the particle of interest 178 b has been displacedradially, it will flow into the first branch 172 a as was the objectiveof the switching operation.

According to yet another embodiment, the cross-sectional dimensions of amicrochannel including a bubble valve according to the teachings of thepresent invention may be varied locally to affect the pressure withinthe microchannel interior. For example, the microchannel may be narrowedor widened at certain locations to increase or decrease the capillaryforces acting on a fluid in the microchannel interior. One of ordinaryskill in the art will be able to determine a suitable cross-sectionaldimension to achieve a desired pressure within the microchannelinterior.

The bubble valve of the present invention may be implemented in avariety of microfluidic devices used for many applications. In aparticular application, the bubble valve is implemented in aflow-cytometer based instrument for sorting or physically separatingparticles of interest from a sample or for measuring selected physicaland chemical characteristics of cells or particles in suspension as theytravel past a particular site. The bubble valve may also be employed indevices for sequencing or manipulating DNA, medical diagnosticinstruments, devices for drug discovery, chemical analysis and so on.

The present invention provides an improved system and method forregulating fluid flow in a microchannel for a variety of applications.The bubble valve of the present invention is easy to operate andcontrol, simple to manufacture and economical. In addition, the bubblevalve does not adversely affect the liquid in the microchannel. Thebubble valve effectively controls the flow of liquids in microfluidicsystems, without heating the fluid and without complex on-chipcircuitry.

The present invention has been described relative to an illustrativeembodiment. Since certain changes may be made in the above constructionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description or shown in theaccompanying drawings be interpreted as illustrative and not in alimiting sense.

It is also to be understood that the following claims are to cover allgeneric and specific features of the invention described herein, and allstatements of the scope of the invention which, as a matter of language,might be said to fall therebetween.

Having described the invention, what is claimed as new and protected byLetters Patent is:

1. A microfluidic device, comprising: a microchannel having an interiorbounded by a side wall; a valve for regulating the flow of fluid throughthe microchannel, the valve comprising a gas-filled reservoir, a fluidmeniscus interfacing the reservoir and the interior and an actuator forvarying the volume of the reservoir to increase an internal pressure ofthe reservoir to vary the flow of liquid through the channel.
 2. Themicrofluidic device of claim 1, wherein the actuator deflects themeniscus into the microchannel interior to regulate the flow of fluidthrough the microchannel.
 3. The microfluidic device of claim 1, whereinthe meniscus comprises a virtual wall formed in an aperture in the sidewall of the microchannel when the microchannel is filled with a liquid.4. The microfluidic device of claim 1, wherein the actuator generates agas bubble in the microchannel.
 5. The microfluidic device of claim 4,further comprising a hydrophobic patch attached to an inner wall of themicrochannel for anchoring the gas bubble.
 6. The microfluidic device ofclaim 4, wherein the microchannel defines a cavity for retaining the gasbubble.
 7. The microfluidic device of claim 1, wherein the gas filledreservoir comprises a movable membrane.
 8. The microfluidic device ofclaim 7, wherein the actuator deflects the movable membrane to create abubble in the microchannel interior.
 9. A microfluidic devicecomprising: a first plate having a groove formed therein defining amicrochannel; a second plate for enclosing the microchannel bonded tothe first plate having an aperture adjacent to the groove sized anddimensioned to form a meniscus when the microchannel is filled with aliquid, the aperture defining a reservoir adjacent to the microchannel,wherein the meniscus forms an interface between the microchannel and thereservoir; and a flexible membrane bonded to the second plate to sealthe reservoir.
 10. The microfluidic device of claim 9, furthercomprising an actuator for deflecting the flexible membrane, wherein thedeflection of the membrane increases the pressure in the reservoir anddeflects the meniscus into the microchannel to regulate liquid flowtherethrough.
 11. The microfluidic device of claim 9, further comprisinga hydrophobic patch attached to the groove.
 12. The microfluidic deviceof claim 9, wherein the meniscus forms a bubble in the microchannel toblock liquid flow.
 13. A method of making a bubble valve, comprising:providing a microchannel having an interior bounded by a side wall, anaperture formed in the side wall and a valve chamber adjacent to theaperture in communication with the interior; filling the microchannelwith a liquid to form a meniscus of the liquid in the aperture, wherebythe step of filling traps a gas in the valve chamber; providing anactuator for increasing the pressure in the valve chamber to deflect themeniscus into the interior.
 14. The method of claim 13, wherein the stepof providing an actuator comprises applying and sealing an actuatorcomprising a chamber to a top surface of the microchannel to form agas-filled chamber adjacent to the meniscus, wherein the actuator variesthe pressure in the gas-filled chamber to deflect the meniscus into theinterior, thereby regulating fluid flow.
 15. A method of varying anelectrical resistance in a microchannel, comprising the steps of:generating a bubble; injecting the bubble into a liquid in themicrochannel, whereby the bubble varies the electrical resistance of themicrochannel.
 16. The method of claim 15, wherein the step of generatinga bubble comprises applying a pressure to a meniscus formed in a sidewall of the microchannel, wherein the meniscus is formed by the liquidin the microchannel filling an aperture in the side wall.
 17. The methodof claim 16, wherein the step of applying a pressure comprisesincreasing the pressure within a sealed reservoir formed adjacent to theaperture.
 18. An electrophoretic system, comprising a firstelectrokinetically operated microchannel; a sample well for providing asample to the first electrokinetically operated microchannelmicrochannel; a voltage source; a bubble valve for injecting a bubbleinto the microchannel to vary the electrical resistance of themicrochannel.
 19. The electrophoretic system of claim 18, furthercomprising: a second electrokinetically operated microchannel incommunication with the first electrokinetically operated microchannel,wherein the a bubble valve selectively blocks flow from the firstelectrokinetically operated microchannel to the secondelectrokinetically operated microchannel by selectively injecting abubble into a microchannel.